The reduced solubility of deoxygenated sickle hemoglobin leads to aggregation or polymerization of hemoglobin in sickle hemoglobin containing erythrocytes which can lead to abnormal rheology. Variation in the amount of sickle hemoglobin produced in the erythrocyte is influenced by the production of other hemoglobins particularly in the case of sickle trait and other sickle cell syndromes. The extent of polymerization of sickle hemoglobin is determined by oxygen saturation, hemoglobin concentration and hemoglobin composition. A detailed analysis of the solubility of mixtures of hemoglobin at various oxygen saturations provides the means to predict the maximum extent of polymerization within the sickle hemoglobin containing erythrocyte. A method to measure directly the equilibrium solubility of sickle hemoglobin mixtures with other hemoglobins at various oxygen saturations was developed. These measurements show that the solubility increases with increasing amounts of fetal hemoglobin at 0.32 g/dl per percent fetal hemoglobin. The solubility increases with ligand concentration as the critical oxygen saturation above which no polymer is detected is shifted to lower ligand concentrations as the percent fetal hemoglobin increases. A model has been developed using hydrodynamic lubrication theory to estimate the contributions of polymer and membrane changes to the impaired rheology of sickle erythrocytes. Predictions of intracellular sickle hemoglobin polymerization tendency have been found to correlate strongly with severity of hemolysis in different sickle syndromes. Analysis of 2674 individuals with sickle cell anemia from the Cooperative Study of Sickle Cell Disease database indicate that polymerization tendency rises continuously during the first twelve years of life, due to continuous decrease in fetal hemoglobin and increase in mean corpuscular hemoglobin concentration until adolescence, and then becomes relatively constant. In general, males had higher polymerization tendencies than females, and individuals with alpha-thalassemia had lower values than those without alpha-thalassemia. Polymerization tendency had a strong inverse correlation with hematocrit and correlated positively with frequency of pain crisis. These analyses may allow prediction of disease severity within cohorts of sickle cell anemia patients and provide a basis for evaluating therapeutic strategies designed to decrease intracellular sickle hemoglobin polymerization.